1. Field of the Invention
The present invention relates to novel antimycobacterial compounds and in particular to antimycobacterial compounds comprised of Schiff base, diacylhydrazine, sulfur-containing diacylhydrazine and oxadiazoline congeners of isonicotinic acid hydrazide. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
2. Description of the Related Art
The occurrence of some three million new cases of tuberculosis per year world-wide and the emergence of new strains of Mycobacterium tuberculosis characterized by drug resistance or increased virulence have created the need for the evolution of newer and more powerful drugs, the re-examination and re-evaluation of prior art drugs and the detailed elucidation of the mechanisms of action of antimycobacterial compounds.
In the United States there has been an increase in the incidence of tuberculosis between 1985 and 1992. As many as 15 million persons in the United States are probably infected but are not yet symptomatic. These persons may develop active disease, and their risk for so doing increases when coinfected with the human immunodeficiency virus (HIV). Infection with Mycobacterium tuberculosis is observed to a significant extent among acquired immune deficiency syndrome (AIDS) patients or among individuals undergoing immunosuppressive therapy. Significantly, tuberculosis accelerates the natural history of HIV, particularly in the early stages of infection, resulting in an increased viral load. Tuberculosis may generate a nurturing microenvironment for HIV, enhancing viral replication. While many cases of disease due to pathogenic mycobacteria are caused by Mycobacterium tuberculosis (MTB), several other mycobacterial diseases have begun to emerge, caused by nontuberculous mycobacteria (NTB). These include diseases caused by Mycobacterium avium, M. ulcerans, M. marinum and M. haemophilum. These NTM diseases are considered important opportunistic infections (OIs) in patients with AIDS, but the rates of non-AIDS-associated NTB infections are also on the rise.
An absence of activity by those skilled in the art in the area of new drug development extending over a period of approximately 35 years has led to minimal research relating to the design of new antimycobacterial agents. This lack of research is a result of the usefulness and efficacy of prior art drugs such as isoniazid (INH, the most widely used antimycobacterial drug), ethambutol, rifampin and pyrazinamide. Combination therapy involving these drugs, especially when prescribed as one component of a broader therapeutic regimen such as directly-observed short-course therapy (DOTS), has been highly effective. When the goal of the elimination of tuberculosis seemed achievable, based largely on these effective drugs and improving standards of nutrition, hygiene and public health, little impetus remained for research.
Today, it is clear that increased research on drug design has been necessary to recapture lost ground and to make new advances. To facilitate the development of new antimycobacterials, those skilled in the art have recently begun to place strong emphasis on the identification of the targets of existing drugs and on those characteristics of pathogen cell wall structure that play a role in limiting drug effectiveness. Billington et al., Synthesis and Antimycobacterial Activity of Some Heteroarylcarboxamidrazone Derivatives. Drug Design and Discovery. 15:269-275 (1998); Setlow P., Survival of Dormant Spores of Bacillus Species for Years and Years and . . . How Do They Do It? The Nucleus. LXIII:5 (1995); Wallis et al., Drug Tolerance in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy. 43(11):2600-2606 (1999). For example, one target enzyme for INH is a long-chain enoyl-acyl carrier protein (ACP) reductase (InhA). This enzyme is important for the biosynthesis of mycolic acids, alpha-branched fatty acids containing as many as 90 carbon atoms, crucial components of mycobacterial cell walls. Asselineau, J. et al., Chemical Structure and Biological Activity of Mycolic Acids, p. 14ff, 40. In C. Wolstenholme, M. Cameron, and C. O'Connor (ed.), Ciba Foundation Symposium on Experimental Tuberculosis: Bacillus and Host (with an Addendum on Leprosy)(1955); Brennan, P. et al., The Envelope of Mycobacteria. Annual Reviews in Biochemistry. 64:29-63 (1995).
The present invention provides novel Schiff base, diacylhydrazine, sulfur-containing diacylhydrazine and oxadiazoline congeners of isonicotinic acid hydrazide that have increased lipophilicity and inhibit mycolate biosynthesis.
In addition to the need for the evolution of newer and more powerful antimycobacterial drugs, the biological evaluation of compounds suspected to be active against mycobacteria requires that the compounds be readily available in pure form on quantity scale, generally understood to be gram or multi-gram scale, as opposed to milligram scale. Gram scale quantities are necessary for the large numbers of biological tests which must be performed and replicated for the evaluation of a new drug candidate.
Products of synthetic reactions are most desirable when they can be easily and cheaply obtained as dry and free-flowing solids. In the long run, dry and free-flowing solids permit better formulations of drugs as tablets, capsules or syrups. The invention disclosed herein provides a novel method of Schiff base synthesis which yields products directly as dry free-flowing solids in analytically pure form. The products of the prior art syntheses are obtained as intractable oils which are difficult and labor-intensive to purify or bring into dry free-flowing form. The present invention overcomes these drawbacks and provides syntheses of Schiff base, diacylhydrazine, sulfur-containing diacylhydrazine and oxadiazoline congeners of isonicotinic acid hydrazide, which yield products that are suitable for biological evaluation.